Visna of sheep and HIV encephalopathy are chronic neurological diseases caused by ovine and human lentiviruses. The viruses are species-specific and cause infection host to host and in the brain by invasion of infected cells across mucosal surfaces and across the blood-brain-barrier, respectively. Neuropathogenesis is associated with virus replication in macrophages in brain but the mechanism for destruction of the neuropil is not understood. Experiments outlined in this proposal will determine the feasibility of inducing protective immunity in sheep against virus invasion across mucosal surfaces and across the blood-brain-barrier. Inactivated virus particles will be compared for efficacy with recently developed transgenic sheep PBMC which express the virus envelope protein as well as allotypic MHC antigens. Experiments will determine whether immunization of sheep via the intratracheal and the GI routes, respectively, will induce protection at both sites against infected cells and whether protective, group-specific immunity (against heterologous virus) can be induced. Because of the similarity between the two lentiviral systems in the mucosal mode of infection, the sheep experiments will be of value in identifying possible strategies for controlling heterosexual spread of HIV. Various factors (identified in preliminary experiments) that contribute to neuropathogenesis will be explored. The effects of rupture of the vascular endothelium of the brain by physical and pathogenic autoimmune (EAE) processes and the effects of cytokine-induced expression of adhesion and MHC II antigens in the cultured vascular endothelial cells will be explored. Infection in the bone marrow will be evaluated to confirm that this event precedes traffic of infected cells across the BBB and that the severity of infection in precursor cells in the marrow influences the rate of entry of virus-infected cells into the brain. Antibodies to viral, leukocyte and other cellular antigens will be delivered into brains of infected sheep via ventricular access devices to determine whether modulation of trafficking of specific mononuclear cells or expression of specific cellular antigens will affect CNS lesions and virus replication. Finally, the viral genetic basis of tissue- specific virulence will be determined using an infectious molecular clone of visna virus which will have mutated and become tropic for a particular tissue during virus passage through he specific tissue, in sequentially inoculated sheep.